Combined Treatment With Sustained-Release Basic Fibroblast Growth Factor and Heparin Enhances Neovascularization in Hypercholesterolemic Mouse Hindlimb Ischemia

Arai, Yoshinori; Fujita, Masatoshi; Marui, Akira; Hirose, Katsumi; Sakaguchi, Hisashi; Ikeda, Tadashi; Tabata, Yasuhiko; Komeda, Masashi

doi:10.1253/circj.71.412

Cited by 17 publications

(38 citation statements)

References 37 publications

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“…[1][2][3][4][5][6][7][8]19,20 Briefly, gelatin hydrogelmicrospheres were prepared by crosslinking glutaraldehyde of gelatin in the dispersed state. Human recombinant bFGF was incorporated into the gelatin microspheres by dropping 20 l of bFGF solution at various concentrations into 2 mg of freeze-dried gelatin microspheres; the microspheres were then left at room temperature for 3 h. At use, the bFGF containing gelatin hydrogel microspheres were dispersed in 100 l of phosphate buffer saline, aspirated into a 1-ml syringe attached with a 27-G needle (TERUMO, Tokyo, Japan), and injected into the 5 sites of ischemic thigh muscles of mice hindlimb.…”

Section: Preparation Of Gelatin Hydrogel Microspheres Incorporating Bfgfmentioning

confidence: 99%

“…[5][6][7] To eliminate the influence of the surgical procedure, the average blood perfusion of the bilateral feet was evaluated. To minimize influential variables including ambient light and temperature, perfusion was expressed as the ratio of the blood perfusion in the right (ischemic) limb to that in the left (non-ischemic) limb of the same mouse, that is, in terms of the LDPI index (LDPII).…”

Section: Measurement Of Hindlimb Blood Perfusionmentioning

confidence: 99%

“…To minimize influential variables including ambient light and temperature, perfusion was expressed as the ratio of the blood perfusion in the right (ischemic) limb to that in the left (non-ischemic) limb of the same mouse, that is, in terms of the LDPI index (LDPII). [5][6][7]24 Immunohistochemistry Four weeks after the initiation of treatment, the mice were euthanized and perfusion-fixed with 4% paraformaldehyde. [5][6][7] The ischemic calf muscles were embedded in optimal cutting temperature compound (Sakura Finetechnical, Tokyo, Japan) and frozen at -80°C.…”

Section: Measurement Of Hindlimb Blood Perfusionmentioning

confidence: 99%

“…[5][6][7]24 Immunohistochemistry Four weeks after the initiation of treatment, the mice were euthanized and perfusion-fixed with 4% paraformaldehyde. [5][6][7] The ischemic calf muscles were embedded in optimal cutting temperature compound (Sakura Finetechnical, Tokyo, Japan) and frozen at -80°C. Cryostat sections (5-m thick) of the tissues were stained with rabbit polyclonal antihuman von Willebrand factor antibody (vWF; Dako Japan, Kyoto, Japan) or mouse monoclonal anti-human smooth muscle actin antibody (SMA; Sigma-Aldrich Japan K.K., Tokyo, Japan).…”

Section: Measurement Of Hindlimb Blood Perfusionmentioning

confidence: 99%

“…The mature vessel density was calculated by counting the number of of SMA-positive vessels. [5][6][7] …”

Section: Measurement Of Hindlimb Blood Perfusionmentioning

confidence: 99%

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Sustained Release of Prostaglandin E1 Potentiates the Impaired Therapeutic Angiogenesis by Basic Fibroblast Growth Factor in Diabetic Murine Hindlimb Ischemia

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Section: Preparation Of Gelatin Hydrogel Microspheres Incorporating Bfgfmentioning

confidence: 99%

Section: Measurement Of Hindlimb Blood Perfusionmentioning

confidence: 99%

Section: Measurement Of Hindlimb Blood Perfusionmentioning

confidence: 99%

Section: Measurement Of Hindlimb Blood Perfusionmentioning

confidence: 99%

“…The mature vessel density was calculated by counting the number of of SMA-positive vessels. [5][6][7] …”

Section: Measurement Of Hindlimb Blood Perfusionmentioning

confidence: 99%

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Sustained Release of Prostaglandin E1 Potentiates the Impaired Therapeutic Angiogenesis by Basic Fibroblast Growth Factor in Diabetic Murine Hindlimb Ischemia

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et al. 2008

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Safety and efficacy of sustained release of basic fibroblast growth factor using gelatin hydrogel in patients with critical limb ischemia

et al. 2015

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As a form of therapeutic angiogenesis, we sought to investigate the safety and efficacy of a sustained-release system of basic fibroblast growth factor (bFGF) using biodegradable gelatin hydrogel in patients with critical limb ischemia (CLI). We conducted a phase I-IIa study that analyzed 10 CLI patients following a 200-μg intramuscular injection of bFGF-incorporated gelatin hydrogel microspheres into the ischemic limb. Primary endpoints were safety and transcutaneous oxygen pressure (TcO2) at 4 and 24 weeks after treatment. During the follow-up, there was no death or serious procedure-related adverse event. After 24 weeks, TcO2 (28.4 ± 8.4 vs. 46.2 ± 13.0 mmHg for pretreatment vs after 24 weeks, p < 0.01) showed significant improvement. Regarding secondary endpoints, the distance walked in 6 min (255 ± 105 vs. 318 ± 127 m, p = 0.02), the Rutherford classification (4.4 ± 0.5 vs. 3.1 ± 1.4, p = 0.02), the rest pain scale (1.7 ± 1.0 vs. 1.2 ± 1.3, p = 0.03), and the cyanotic scale (2.0 ± 1.1 vs. 0.9 ± 0.9, p < 0.01) also showed improvement. The blood levels of bFGF were within the normal range in all patients. A subanalysis of patients with arteriosclerosis obliterans (n = 7) or thromboangiitis obliterans (Buerger's disease) (n = 3) revealed that TcO2 had significantly improved in both subgroups. TcO2 did not differ between patients with or without chronic kidney disease. The sustained release of bFGF from biodegradable gelatin hydrogel may offer a safe and effective form of angiogenesis for patients with CLI.

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Enhanced angiogenesis by multiple release of platelet-rich plasma contents and basic fibroblast growth factor from gelatin hydrogels

2012

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The objective of this study is to evaluate the angiogenic effects induced by biodegradable gelatin hydrogel granules incorporating mixed platelet-rich plasma (PRP) growth factor mixture (PGFM) and bioactive basic fibroblast growth factor (bFGF). The PRP was prepared by a double-spinning technique for isolating animal bloods, followed by treatment with different concentrations of calcium chloride (CaCl(2)) solution. The CaCl(2) solution treatment activated the platelets of PRP, allowing the release of various growth factors, such as platelet-derived growth factor (PDGF)-BB, vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β(1), and epithelial growth factor (EGF). In the PRP treated with different CaCl(2) solutions, high amounts of representative platelet growth factor, PDGF-BB, VEGF, EGF, and TGF-β(1) were detected in the CaCl(2) concentrations of 1, 2, and 4 wt.% compared with higher or lower ones. The PRP treated was impregnated into gelatin hydrogel granules freeze-dried at 37°C for 1h, and then the percentage of PGFM desorbed from the gelatin hydrogel granules was evaluated. The percentages of PDGF-BB, VEGF, EGF, and TGF-β(1) desorbed tended to decrease with decreasing CaCl(2) concentration. Taken together, the CaCl(2) concentration to activate PRP for PGFM release was fixed at 2 wt.%. In vitro release tests demonstrated that the PGFM was released from the gelatin hydrogel granules with time. For the gelatin hydrogels incorporating PGFM and bFGF, the time profile of PDGF-BB or bFGF release was in good correspondence with that of gelatin hydrogel degradation. The gelatin hydrogel granules incorporating mixed PGFM and bFGF were prepared and intramuscularly injected to a mouse leg ischemia model to evaluate the angiogenic effects in terms of histological and laser Doppler perfusion imaging examinations. As controls, hydrogel granules incorporating bFGF, PGFM, and platelet-poor plasma were used for the angiogenic evaluation. The number of blood vessels newly formed and the percentage of anti-α-smooth muscle actin antibody-positive cells increased around ischemic sites injected with the gelatin hydrogel granules incorporating mixed PGFM and bFGF, in marked contrast to other control groups. The blood reperfusion level of ischemic tissues was enhanced by the hydrogel granules incorporating mixed PGFM and bFGF, whereas no enhancement was observed for other groups. It is concluded that the dual-release system of PGFM and bFGF from gelatin hydrogel granules shows promise as a method to enhance angiogenic effects.

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Combined Treatment With Sustained-Release Basic Fibroblast Growth Factor and Heparin Enhances Neovascularization in Hypercholesterolemic Mouse Hindlimb Ischemia

Cited by 17 publications

References 37 publications

Sustained Release of Prostaglandin E1 Potentiates the Impaired Therapeutic Angiogenesis by Basic Fibroblast Growth Factor in Diabetic Murine Hindlimb Ischemia

Sustained Release of Prostaglandin E1 Potentiates the Impaired Therapeutic Angiogenesis by Basic Fibroblast Growth Factor in Diabetic Murine Hindlimb Ischemia

Safety and efficacy of sustained release of basic fibroblast growth factor using gelatin hydrogel in patients with critical limb ischemia

Enhanced angiogenesis by multiple release of platelet-rich plasma contents and basic fibroblast growth factor from gelatin hydrogels

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